1. Field of the Invention
This invention relates to methods of treating patients suffering from chronic pain or chronic cough without provoking intestinal dysmotility.
2. Description of the Prior Art
The treatment of patients suffering from severe, chronic pain or chronic cough presents a number of serious clinical difficulties. Narcotic or opioid analgesic agents, such as morphine, methadone, codeine, meperidine and oxycodone are often administered to such patients, e.g. patients suffering from progressive cancer, pulmonary diseases, degenerative joint disease and chronic abdominal pain. However, apart from other undesirable side effects of long-term opioid administration, it is well known that chronic usage of long-acting opioid analgesics results in severe constipation and other symptoms of intestinal hypomotility. Although it is believed that tolerance to the constipating effects of chronic narcotic administration does eventually develop, it develops extremely slowly. Indeed, development of tolerance may be of little significance in the case of many elderly or terminal patients because of the limiting time factors or because doses of analgesic must normally be increased as tolerance develops to their analgesic effects.
The constipation and other symptoms of intestinal hypomotility caused by administration of opioid analgesics for chronic pain or cough not only create discomfort for the patient but may also complicate both the treatment program and the patient's underlying condition. In fact, chronic constipation may cause new health risks in and of itself, such as for cardiac patients and geriatric patients.
Traditional methods of relieving constipation in patients on long-term opioid analgesic regimens include the administration of a variety of laxatives, purgatives, stool softeners and lubricants, the regulation of diet, and the like. In some cases, the discomfort and potential danger of intestinal rupture created by constipation may become the limiting factor in the treatment of the pain and the doses of analgesic may have to be held constant at a given level or even reduced in an attempt to improve intestinal motility.
It has been proposed that certain opioid antagonists which have substantial systemic activity upon oral administration might be utilized to counteract the intestinal hypomotility provoked by long term administration of opioid agonists. Of course, in order to be of practical use, any such antagonists to be orally administered as adjuncts to analgesic or antitussive agents must not substantially interfere with the analgesic or antitussive effects of the opioid agonists administered to relieve pain or reduce cough. Thus, in U.S. Pat. No. 4,176,186, a family of compounds constituting quaternary derivatives of noroxymorphone are disclosed as being useful to prevent or relieve the intestinal motility-inhibiting side effects of narcotic analgesics without interfering with their analgesic activity.
The compounds disclosed in U.S. Pat. No. 4,176,186 and similar agents suggested in the prior art for alleviating the constipation problems of chronic pain patients suffer from a number of drawbacks. Although these substances do not cross the blood-brain barrier, and therefore do not substantially interfere with those analgesic effects of the opioid agents that are mediated through the brain, the antagonists suggested by the prior art may well interfere with analgesic activity mediated through the spinal cord, the peripheral sensory system, the pituitary gland and possibly the basal hypothalamus, all of which are believed to contain important opioid receptors. In addition, quaternary antagonists have low affinity for opioid receptors, including the gut receptors, and thus are not effective in counteracting narcotic induced-intestinal hypomotility. Furthermore, the prior art quaternary antagonist compounds have been found to have an unacceptably high degree of toxicity, making them particularly unsuitable for long term administration to chronic pain patients. No feasible or satisfactory method of treating chronic pain or cough patients utilizing the quaternary compounds has ever been disclosed.
In short, no safe, effective and practical means for alleviating the serious complication of intestinal hypomotility in chronic pain or cough patients undergoing opioid therapy has been heretofore developed, notwithstanding the long felt clinical need for such means.